Human Gene Module / Chromosome 10 / ITGA8

ITGA8integrin subunit alpha 8

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 7
Rare Variants / Common Variants
15 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
10p13
Associated Disorders
-
Relevance to Autism

De novo variants in the ITGA8 gene have been identified in ASD probands, including two de novo missense variants in probands from the Simons Simplex Collection and the Autism Sequencing Consortium (Iossifov et al., 2014; Yuen et al., 2017; Turner et al., 2017; Satterstrom et al., 2020). Functional assessment of the ASD-associated p.Arg748Cys missense variant, which was originally identified in a proband from the Simons Simplex Collection, in Drosophila using an overexpression-based strategy in Macrogliese et al., 2022 demonstrated that flies overexpressing ITGA8-p.Arg748Gly failed to reduce the expected viability to the extent of the corresponding reference allele upon overexpression, indicating a loss-of-function effect.

Molecular Function

Integrins are heterodimeric transmembrane receptor proteins that mediate numerous cellular processes including cell adhesion, cytoskeletal rearrangement, and activation of cell signaling pathways. Integrins are composed of alpha and beta subunits. This gene encodes the alpha 8 subunit of the heterodimeric integrin alpha8beta1 protein. The encoded protein is a single-pass type 1 membrane protein that contains multiple FG-GAP repeats. This repeat is predicted to fold into a beta propeller structure. This gene regulates the recruitment of mesenchymal cells into epithelial structures, mediates cell-cell interactions, and regulates neurite outgrowth of sensory and motor neurons. The integrin alpha8beta1 protein thus plays an important role in wound-healing and organogenesis. Mutations in this gene have been associated with renal hypodysplasia/aplasia-1 (RHDA1) and with several animal models of chronic kidney disease.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ITGA8 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Recent Recommendation - Marcogliese PC et al. (2022) Yes -
6 Support - Zhou X et al. (2022) Yes -
7 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.802+11T>C - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.343+5778A>G - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.344-3251G>C - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.2919C>T p.Ser973%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1354+1185A>G - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.2212-1110G>C - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1400-7670C>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.2835+3464G>A - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.569-911C>G - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1354+10346A>C - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.802+5670T>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.2671A>T p.Ser891Cys missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.2242C>T p.Arg748Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1354+11140_1354+11179del - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.118_119insTTCA p.Asn40IlefsTer74 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49516650684712

Ranking 3151/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 5.0188601278335E-8

Ranking 15840/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.81733926946673

Ranking 2547/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.23429256543428

Ranking 3703/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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